2 DOSAGE AND ADMINISTRATION

2.1 Important Safety Instructions

LUTATHERA is a radiopharmaceutical; handle with appropriate safety measures to minimize radiation exposure [see Warnings and Precautions (5.1)]. Use waterproof gloves and effective radiation shielding when handling LUTATHERA. Radiopharmaceuticals, including LUTATHERA, should be used by or under the control of healthcare providers who are qualified by specific training and experience in the safe use and handling of radiopharmaceuticals, and whose experience and training have been approved by the appropriate governmental agency authorized to license the use of radiopharmaceuticals.

Verify pregnancy status of females of reproductive potential prior to initiating LUTATHERA [see Use in Specific Populations (8.1, 8.3)].

Monitor patients closely for signs and symptoms of hypersensitivity reactions during and following the LUTATHERA administration for a minimum of 2 hours in a setting where cardiopulmonary resuscitation medication and equipment are available [see Warnings and Precautions (5.6)].

2.2 Recommended Dosage

The recommended LUTATHERA dosage for adult and pediatric patients 12 years and older is 7.4 GBq (200 mCi) every 8 weeks (± 1 week) for a total of 4 doses. Administer premedications and concomitant medications as recommended [see Dosage and Administration (2.3)].

2.3 Premedications and Concomitant Medications

Somatostatin Analogs

Before initiating LUTATHERA treatment: Discontinue long-acting somatostatin analogs (e.g., long-acting octreotide) at least 4 weeks prior to initiating LUTATHERA. Administer short-acting octreotide as needed; discontinue at least 24 hours prior to initiating LUTATHERA [see Drug Interactions (7.1)].
During LUTATHERA treatment: Administer long-acting octreotide 30 mg intramuscularly between 4 to 24 hours after each LUTATHERA dose. Do not administer long-acting octreotide within 4 weeks prior to each subsequent LUTATHERA dose. Short-acting octreotide may be given for symptomatic management during LUTATHERA treatment but must be withheld at least 24 hours before each LUTATHERA dose.
Following LUTATHERA treatment: Continue long-acting octreotide 30 mg intramuscularly every 4 weeks after completing LUTATHERA until disease progression or for 18 months following treatment initiation at the discretion of the physician.

Antiemetics

Administer antiemetics before the recommended amino acid solution.

Amino Acid Solution

Initiate an intravenous infusion of a sterile amino acid solution containing L-lysine and L-arginine (Table 1) 30 minutes before the start of the LUTATHERA infusion. Use a three-way valve to administer the amino acid solution using the same venous access as LUTATHERA or administer the amino acid solution through a separate venous access in the patient’s other arm. Continue the amino acid solution infusion during and for at least 3 hours after completion of the LUTATHERA infusion. Do not decrease the dose of the amino acid solution if a reduced dose of LUTATHERA is administered [see Warnings and Precautions (5.4)].

Table 1. Amino Acid Solution
Item	Specification
aequivalent to 14.4 to 20 g L-lysine. bequivalent to 14.9 to 20.7 g L-arginine.
L-lysine HCl	Between 18 and 25 ga
L-arginine HCl	Between 18 and 25 gb
Volume	1 to 2 L
Osmolality	< 1200 mOsmol/kg

Hypersensitivity Prophylaxis

Premedicate patients who have had prior Grade 1 or 2 hypersensitivity reactions to LUTATHERA. Do not re-challenge patients who experience Grade 3 or 4 hypersensitivity reactions to LUTATHERA [see Warnings and Precautions (5.6)].

2.4 Dosage Modifications for Adverse Reactions

Recommended dose modifications of LUTATHERA for adverse reactions are provided in Table 2.

Table 2. Recommended Dosage Modifications of LUTATHERA for Adverse Reactions
aGrading of severity is defined in the most current Common Terminology Criteria for Adverse Events (CTCAE). bIncluding allergic reaction and anaphylaxis. cNo dose modification required for hematological toxicities Grade 3 or Grade 4 solely due to lymphopenia.
Adverse reaction	Severity of adverse reactiona	Dose modification
Thrombocytopenia [see Warnings and Precautions (5.2)]	First occurrence of Grade 2, 3, or 4	Withhold dose until complete or partial resolution (Grade 0 to 1). Resume LUTATHERA at 3.7 GBq (100 mCi) in patients with complete or partial resolution. If reduced dose does not result in Grade 2, 3, or 4 thrombocytopenia, administer LUTATHERA at 7.4 GBq (200 mCi) as next dose. Permanently discontinue LUTATHERA for Grade 2 or higher thrombocytopenia requiring a dosing interval beyond 16 weeks.
Thrombocytopenia [see Warnings and Precautions (5.2)]	Recurrent Grade 2, 3, or 4	Permanently discontinue LUTATHERA.
Anemia and Neutropenia [see Warnings and Precautions (5.2)]	First occurrence of Grade 3 or 4	Withhold dose until complete or partial resolution (Grade 0, 1, or 2). Resume LUTATHERA at 3.7 GBq (100 mCi) in patients with complete or partial resolution. If reduced dose does not result in Grade 3 or 4 anemia or neutropenia, administer LUTATHERA at 7.4 GBq (200 mCi) as next dose. Permanently discontinue LUTATHERA for Grade 3 or higher anemia or neutropenia requiring a dosing interval beyond 16 weeks.
Anemia and Neutropenia [see Warnings and Precautions (5.2)]	Recurrent Grade 3 or 4	Permanently discontinue LUTATHERA.
Renal Toxicity [see Warnings and Precautions (5.4)]	First occurrence of: Creatinine clearance less than 40 mL/min; calculated using Cockcroft-Gault formula with actual body weight, or 40% increase from baseline serum creatinine, or 40% decrease from baseline creatinine clearance; calculated using Cockcroft-Gault formula with actual body weight.	Withhold dose until resolution or return to baseline. Resume LUTATHERA at 3.7 GBq (100 mCi) in patients with resolution or return to baseline. If reduced dose does not result in renal toxicity, administer LUTATHERA at 7.4 GBq (200 mCi) as next dose. Permanently discontinue LUTATHERA for renal toxicity requiring a dosing interval beyond 16 weeks.
Renal Toxicity [see Warnings and Precautions (5.4)]	Recurrent renal toxicity	Permanently discontinue LUTATHERA.
Hepatotoxicity [see Warnings and Precautions (5.5)]	First occurrence of: Bilirubinemia greater than 3 times the upper limit of normal (Grade 3 or 4), or Serum albumin less than 30 g/L with international normalized ratio (INR) > 1.5.	Withhold dose until resolution or return to baseline. Resume LUTATHERA at 3.7 GBq (100 mCi) in patients with resolution or return to baseline. If reduced LUTATHERA dose does not result in hepatotoxicity, administer LUTATHERA at 7.4 GBq (200 mCi) as next dose. Permanently discontinue LUTATHERA for hepatotoxicity requiring a dosing interval beyond 16 weeks.
Hepatotoxicity [see Warnings and Precautions (5.5)]	Recurrent hepatotoxicity	Permanently discontinue LUTATHERA.
Hypersensitivity Reactionsb [see Warnings and Precautions (5.6)]	First occurrence of Grade 3 or 4	Permanently discontinue LUTATHERA.
Any Other Adverse Reactionsc [see Adverse Reactions (6.1)]	First occurrence of Grade 3 or 4	Withhold dose until complete or partial resolution (Grade 0 to 2). Resume LUTATHERA at 3.7 GBq (100 mCi) in patients with complete or partial resolution. If reduced dose does not result in Grade 3 or 4 toxicity, administer LUTATHERA at 7.4 GBq (200 mCi) as next dose. Permanently discontinue LUTATHERA for Grade 3 or higher adverse reactions requiring a dosing interval beyond 16 weeks.
Any Other Adverse Reactionsc [see Adverse Reactions (6.1)]	Recurrent Grade 3 or 4	Permanently discontinue LUTATHERA.

2.5 Preparation and Administration

Preparation Instructions

Use aseptic technique and radiation shielding when handling or administering the LUTATHERA solution. Use tongs when handling the vial to minimize radiation exposure.
Inspect the product visually under a shielded screen for particulate matter and discoloration prior to administration. Discard the vial if particulates and/or discoloration are present.
Do not inject the LUTATHERA solution directly into any other intravenous solution.
Confirm the amount of radioactivity of LUTATHERA delivered to the patient with an appropriate dose calibrator prior to and after each LUTATHERA administration.
Dispose of any unused medicinal product or waste material in accordance with local and federal laws.

Administration Instructions

Prior to administration, flush the intravenous catheter used for LUTATHERA administration with ≥ 10 mL of 0.9% Sodium Chloride Injection, USP to ensure patency and to minimize the risk of extravasation. Manage cases of extravasation as per institutional guidelines.
The gravity method, peristaltic pump method, or the syringe pump method may be used for the administration of the recommended dosage. Do not administer LUTATHERA as an intravenous bolus.
When using the gravity or peristaltic pump method, infuse LUTATHERA directly from its original container.
Use the peristaltic pump or syringe pump method when administering a reduced dose of LUTATHERA following a dosage modification for an adverse reaction. When using the gravity method for a reduced dose, adjust the LUTATHERA dose before the administration to avoid the delivery of an incorrect volume of LUTATHERA.

Intravenous Methods of Administration

Instructions for the Gravity Method

Insert a 2.5 cm, 20-gauge needle (short needle) into the LUTATHERA vial and connect via a catheter to 500 mL 0.9% Sodium Chloride Injection, USP (used to transport the LUTATHERA solution during the infusion). Ensure that the short needle does not touch the LUTATHERA solution in the vial and do not connect this short needle directly to the patient. Do not allow the 0.9% Sodium Chloride Injection, USP to flow into the LUTATHERA vial prior to the initiation of the LUTATHERA infusion and do not inject the LUTATHERA solution directly into the 0.9% Sodium Chloride Injection, USP.
Insert a second needle that is 9 cm, 18-gauge (long needle) into the LUTATHERA vial ensuring that this long needle touches and is secured to the bottom of the LUTATHERA vial during the entire infusion. Connect the long needle to the patient by an intravenous catheter that is pre-filled with 0.9% Sodium Chloride Injection, USP and that is used for the LUTATHERA infusion into the patient.
Use a clamp or an infusion pump to regulate the flow of the 0.9% Sodium Chloride Injection, USP via the short needle into the LUTATHERA vial at a rate of 50 mL/hour to 100 mL/hour for 5 to 10 minutes and then 200 mL/hour to 300 mL/hour for an additional 25 to 30 minutes (the 0.9% Sodium Chloride Injection, USP entering the vial through the short needle will carry the LUTATHERA solution from the vial to the patient via the intravenous catheter connected to the long needle over a total duration of 30 to 40 minutes).
During the infusion, ensure that the level of solution in the LUTATHERA vial remains constant.
Disconnect the vial from the long needle line and clamp the 0.9% Sodium Chloride Injection, USP line once the level of radioactivity is stable for at least five minutes.
Follow the infusion with an intravenous flush of 25 mL of 0.9% Sodium Chloride Injection, USP through the intravenous catheter to the patient.

Instructions for the Peristaltic Pump Method

Insert a filtered 2.5 cm, 20-gauge needle (short venting needle) into the LUTATHERA vial. Ensure that the short needle does not touch the LUTATHERA solution in the vial and do not connect this short needle directly to the patient or to the peristaltic pump.
Insert a second needle that is 9 cm, 18 gauge (long needle) into the LUTATHERA vial ensuring that the long needle touches and is secured to the bottom of the LUTATHERA vial during the entire infusion. Connect the long needle and a 0.9% Sodium Chloride Injection, USP to a 3-way stopcock valve via appropriate tubing.
Connect the output of the 3-way stopcock valve to tubing installed on the input side of the peristaltic pump according to manufacturer’s instructions.
Prime the line by opening the 3-way stopcock valve and pumping the LUTATHERA solution through the tubing until it reaches the exit of the valve.
Prime the intravenous catheter that will be connected to the patient by opening the 3-way stopcock valve to the 0.9% Sodium Chloride Injection, USP and pumping the 0.9% Sodium Chloride Injection, USP until it exits the end of the catheter tubing.
Connect the primed intravenous catheter to the patient and set the 3-way stopcock valve such that the LUTATHERA solution is in line with the peristaltic pump.
Infuse an appropriate volume of LUTATHERA solution over a 30-40 min period to deliver the desired radioactivity.
When the desired LUTATHERA radioactivity has been delivered, stop the peristaltic pump and then change the position of the 3-way stopcock valve so that the peristaltic pump is in line with the 0.9% Sodium Chloride Injection, USP. Restart the peristaltic pump and infuse an intravenous flush of 25 mL of 0.9% Sodium Chloride Injection, USP through the intravenous catheter to the patient.

Instructions for the Syringe Pump Method

Withdraw an appropriate volume of LUTATHERA solution to deliver the desired radioactivity by using a disposable syringe fitted with a syringe shield and a disposable sterile needle that is 9 cm, 18 gauge (long needle). To aid the withdrawal of the solution, a filtered 2.5 cm, 20-gauge needle (short venting needle) can be used to reduce the resistance from the pressurized vial. Ensure that the short needle does not touch the LUTATHERA solution in the vial.
Fit the syringe into the shielded pump and include a 3-way stopcock valve between the syringe and an intravenous catheter pre-filled with 0.9% Sodium Chloride Injection, USP and used for LUTATHERA administration to the patient.
Infuse an appropriate volume of LUTATHERA solution over a 30-40 min period to deliver the desired radioactivity.
When the desired LUTATHERA radioactivity has been delivered, stop the syringe pump and then change the position of the 3-way stopcock valve to flush the syringe with 25 mL of 0.9% Sodium Chloride Injection, USP. Restart the syringe pump.
After the flush of the syringe has been completed, perform an intravenous flush with 25 mL of 0.9% Sodium Chloride Injection, USP through the intravenous catheter to the patient.

2.6 Radiation Dosimetry

The maximum penetration of lutetium-177 in tissue is 2.2 mm and the mean penetration is 0.67 mm.
The mean and standard deviation (SD) of the estimated radiation absorbed doses for adults receiving LUTATHERA are shown in Table 3. The mean and SD of the estimated radiation absorbed doses for pediatric patients 12 years and older receiving LUTATHERA are shown in Table 4.

Table 3. Estimated Radiation Absorbed Dose for LUTATHERA in Adults in NETTER-1
aN = 18 (two patients excluded because the liver absorbed dose was biased by the uptake of the liver metastases). bN = 9 (female patients only). cRed marrow dosimetry estimates were determined using blood radioactivity. dN = 11 (male patients only).
	Absorbed dose per unit activity (Gy/GBq) (N = 20)		Calculated absorbed dose for 4 x 7.4 GBq (29.6 GBq cumulative activity) (Gy)
Organ	Mean	SD	Mean	SD
Adrenals	0.037	0.016	1.1	0.5
Brain	0.027	0.016	0.8	0.5
Breasts	0.027	0.015	0.8	0.4
Gallbladder wall	0.042	0.019	1.2	0.6
Heart wall	0.032	0.015	0.9	0.4
Kidneys	0.654	0.295	19.4	8.7
Livera	0.299	0.226	8.9	6.7
Lower large intestine wall	0.029	0.016	0.9	0.5
Lungs	0.031	0.015	0.9	0.4
Muscle	0.029	0.015	0.8	0.4
Osteogenic cells	0.151	0.268	4.5	7.9
Ovariesb	0.031	0.013	0.9	0.4
Pancreas	0.038	0.016	1.1	0.5
Red marrowc	0.035	0.029	1.0	0.8
Skin	0.027	0.015	0.8	0.4
Small intestine	0.031	0.015	0.9	0.5
Spleen	0.846	0.804	25.1	23.8
Stomach wall	0.032	0.015	0.9	0.5
Testesd	0.026	0.018	0.8	0.5
Thymus	0.028	0.015	0.8	0.5
Thyroid	0.027	0.016	0.8	0.5
Total body	0.052	0.027	1.6	0.8
Upper large intestine wall	0.032	0.015	0.9	0.4
Urinary bladder wall	0.437	0.176	12.8	5.3
Uterusb	0.032	0.013	1.0	0.4

Table 4. Estimated Radiation Absorbed Dose for LUTATHERA in Pediatric Patients 12 Years and Older in NETTER-P
aData are pooled for 8 pediatric patients with somatostatin receptor-positive (SSTR+) tumors, including 4 patients with GEP-NETs. bN = 5 (female patients only). cN = 7 (3 GEP-NET, 4 SSTR+ tumors). Pituitary dosimetry estimates were only performed when pituitary uptake was clearly observed on the planar images. Due to the small size of the pituitary gland, availability for quantification only from planar images and interference from activity in the nasal mucosa, estimates can be associated with a large uncertainty. Pituitary gland absorbed dose estimate includes absorbed dose contributions from activity within the pituitary only, dose contributions from other tissues are not included. dN = 3 (male patients only). eRed marrow dosimetry estimates were determined either using blood radioactivity or by imaging and scaling of a representative region of the lumbar spine.
	Absorbed dose per unit activity (Gy/GBq) (N = 8a)		Calculated absorbed dose for 4 x 7.4 GBq (29.6 GBq cumulative activity) (Gy)
Organ	Mean	SD	Mean	SD
Adrenals	0.045	0.011	1.3	0.3
Brain	0.021	0.006	0.6	0.2
Breastsb	0.018	0.006	0.5	0.2
Esophagus	0.024	0.006	0.7	0.2
Eyes	0.021	0.006	0.6	0.2
Gallbladder wall	0.031	0.011	0.9	0.3
Heart wall	0.024	0.006	0.7	0.2
Kidneys	0.773	0.288	22.9	8.5
Left colon	0.265	0.081	7.8	2.4
Liver	0.216	0.231	6.4	6.8
Lungs	0.024	0.006	0.7	0.2
Osteogenic cells	0.046	0.019	1.4	0.6
Ovariesb	0.026	0.007	0.8	0.2
Pancreas	0.027	0.007	0.8	0.2
Pituitaryc	1.053	0.348	31.2	10.3
Prostated	0.026	0.006	0.8	0.2
Rectum	0.272	0.085	8.0	2.5
Red marrow (blood)e	0.027	0.005	0.8	0.2
Red marrow (image) e	0.055	0.026	1.6	0.8
Right colon	0.152	0.045	4.5	1.3
Salivary glands	0.036	0.017	1.1	0.5
Small intestine	0.046	0.013	1.3	0.4
Spleen	0.733	0.304	21.7	9.0
Stomach wall	0.027	0.007	0.8	0.2
Testesd	0.021	0.005	0.6	0.2
Thymus	0.022	0.006	0.7	0.2
Thyroid	0.022	0.006	0.6	0.2
Total body	0.042	0.010	1.2	0.3
Urinary bladder wall	0.573	0.088	17.0	2.6
Uterusb	0.031	0.008	0.9	0.2